Preclinical pharmacokinetic evaluation to facilitate repurposing of tyrosine kinase inhibitors nilotinib and imatinib as antiviral agents.

BACKGROUND: Several tyrosine kinase inhibitors (TKIs) developed as anti-cancer drugs, also have anti-viral activity due to their ability to disrupt productive replication and dissemination in infected cells. Consequently, such drugs are attractive candidates for "repurposing" as anti-viral agents. However, clinical evaluation of therapeutics against infectious agents associated with high mortality, but low or infrequent incidence, is often unfeasible. The United States Food and Drug Administration formulated the "Animal Rule" to facilitate use of validated animal models for conducting anti-viral efficacy studies. METHODS: To enable such efficacy studies of two clinically approved TKIs, nilotinib, and imatinib, we first conducted comprehensive pharmacokinetic (PK) studies in relevant rodent and non-rodent animal models. PK of these agents following intravenous and oral dosing were evaluated in C57BL/6 mice, prairie dogs, guinea pigs and Cynomolgus monkeys. Plasma samples were analyzed using an LC-MS/MS method. Secondarily, we evaluated the utility of allometry-based inter-species scaling derived from previously published data to predict the PK parameters, systemic clearance (CL) and the steady state volume of distribution (Vss) of these two drugs in prairie dogs, an animal model not tested thus far. RESULTS: Marked inter-species variability in PK parameters and resulting oral bioavailability was observed. In general, elimination half-lives of these agents in mice and guinea pigs were much shorter (1-3 h) relative to those in larger species such as prairie dogs and monkeys. The longer nilotinib elimination half-life in prairie dogs (i.v., 6.5 h and oral, 7.5 h), facilitated multiple dosing PK and safety assessment. The allometry-based predicted values of the Vss and CL were within 2.0 and 2.5-fold, respectively, of the observed values. CONCLUSIONS: Our results suggest that prairie dogs and monkeys may be suitable rodent and non-rodent species to perform further efficacy testing of these TKIs against orthopoxvirus infections. The use of rodent models such as C57BL/6 mice and guinea pigs for assessing pre-clinical anti-viral efficacy of these two TKIs may be limited due to short elimination and/or low oral bioavailability. Allometry-based correlations, derived from existing literature data, may provide initial estimates, which may serve as a useful guide for pre-clinical PK studies in untested animal models.

Cost-effectiveness of cell saver in short-segment lumbar laminectomy and fusion (≤3 levels).

STUDY DESIGN: Mixed retrospective-prospective cohort study. OBJECTIVE: To characterize practice patterns for the use of Cell Saver at our institution, investigate its cost-effectiveness, and propose a new tool for patient selection. SUMMARY OF BACKGROUND DATA: Blood loss is an exceedingly common complication of spine surgery, and Cell Saver intraoperative cell salvage has been used to decrease reliance on allogeneic blood transfusions for blood volume replacement. The cost-effectiveness of Cell Saver has not been established for lumbar spinal surgery, and no universal guidelines exist for clinicians to decide when to utilize this tool. Other authors have proposed cutoffs for anticipated blood loss volumes which indicate that Cell Saver should be used. METHODS: Five hundred and eight patients undergoing lumbar laminectomy in 3 or fewer levels were reviewed from our prospective spinal outcomes registry. Cost information for Cell Saver and allogeneic transfusions was collected from our institution's billing and collections department. Logistic regression was used to identify patient characteristics associated with use of Cell Saver. An incremental cost effectiveness ratio was calculated based on transfusion and cost data. A clinical prediction score was derived using logistic regression. RESULTS: Use of Cell Saver correlated with increased age, higher body mass index, diabetes, greater American Society of Anesthesiologists classification, and greater number of previous spine surgeries. Outcomes for patients who did and did not have Cell Saver set up intraoperatively were equivocal. Cell Saver was not cost effective based on current usage patterns, but may become cost effective if used for patients with high expected blood loss. A simple clinical prediction rule is proposed which may aid in selection of patients to have Cell Saver present intraoperatively. CONCLUSION: Cell Saver is not a cost-effective intervention but may become cost effective if a threshold of expected intraoperative blood loss is used to select patients more judiciously. LEVEL OF EVIDENCE: 3.

Effects of expectations on loudness and loudness difference.

To determine how expectations affect loudness and loudness difference, in two experiments we induced some subjects to expect loud sounds (condition L), some to expect soft sounds (condition S), and others to have no particular expectations (control). In Experiment 1, all subjects estimated the loudnesses of the same set of three moderately loud 1-kHz tones. Estimates were greatest for subjects in condition S and smallest for subjects in condition L. Control subjects' estimates were intermediate but closer to those of condition S subjects. In Experiment 2, subjects estimated the difference in loudness for pairs of moderately loud 1-kHz tones. Again, estimates were smallest for condition L subjects; estimates were greatest for control subjects, and condition S subjects' estimates were closer to control estimates than to condition L estimates. This pattern of results is explainable by a combination of (1) Parducci's (1995) range-frequency theory and (2) a gain control mechanism in the auditory system under top-down governance (Schneider, Parker, & Murphy, 2011).

Evaluation of disease and viral biomarkers as triggers for therapeutic intervention in respiratory mousepox - an animal model of smallpox.

The human population is currently faced with the potential use of natural or recombinant variola and monkeypox viruses as biological weapons. Furthermore, the emergence of human monkeypox in Africa and its expanding environs poses a significant natural threat. Such occurrences would require therapeutic and prophylactic intervention with antivirals to minimize morbidity and mortality of exposed populations. Two orally-bioavailable antivirals are currently in clinical trials; namely CMX001, an ether-lipid analog of cidofovir with activity at the DNA replication stage and ST-246, a novel viral egress inhibitor. Both of these drugs have previously been evaluated in the ectromelia/mousepox system; however, the trigger for intervention was not linked to a disease biomarker or a specific marker of virus replication. In this study we used lethal, intranasal, ectromelia virus infections of C57BL/6 and hairless SKH1 mice to model human disease and evaluate exanthematous rash (rash) as an indicator to initiate antiviral treatment. We show that significant protection can be provided to C57BL/6 mice by CMX001 or ST-246 when therapy is initiated on day 6 post infection or earlier. We also show that significant protection can be provided to SKH1 mice treated with CMX001 at day 3 post infection or earlier, but this is four or more days before detection of rash (ST-246 not tested). Although in this model rash could not be used as a treatment trigger, viral DNA was detected in blood by day 4 post infection and in the oropharyngeal secretions (saliva) by day 2-3 post infection - thus providing robust and specific markers of virus replication for therapy initiation. These findings are discussed in the context of current respiratory challenge animal models in use for the evaluation of poxvirus antivirals.

Protection for the good: subcategorization reduces hedonic contrast.

Stimuli are rated less "good" when compared to very good context stimuli than when presented alone or compared to less good context stimuli. This diminution in rating is hedonic contrast. In two studies, degree of hedonic contrast depended on subjects' categorization of stimuli. Subjects were surveyed about their liking of gourmet and ordinary coffees (Study 1) and specialty and regular beers (Study 2). In Study 1, contrast was substantially smaller for subjects who regarded the coffees as belonging to different categories than for subjects having a common category for both sorts of coffees. The analogous phenomenon was found in Study 2, comparing subjects who subcategorized beers to subjects who had a common category for both sorts of beers. Contrast is greatest for stimuli in a common category.